- Email: [email protected]
Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans
Accepted Manuscript A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans Max Ward, BS, Antonios Mammis, MD, Maureen T. Barry, MD, Robert F. Heary, MD PII:
S1878-8750(18)30916-1
DOI:
10.1016/j.wneu.2018.04.196
Reference:
WNEU 8032
To appear in:
World Neurosurgery
Received Date: 24 February 2018 Revised Date:
24 April 2018
Accepted Date: 25 April 2018
Please cite this article as: Ward M, Mammis A, Barry MT, Heary RF, A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.04.196. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
M AN U
SC
RI PT
Max Ward 180 West Market Street, Newark NJ, 08807 [email protected] 908-698-3475
A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans Max Ward1 BS, Antonios Mammis1 MD, Maureen T. Barry2 MD, Robert F. Heary1 MD 1 Rutgers-New Jersey Medical School Department of Neurological Surgery Newark, New Jersey Department of Radiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina
AC C
EP
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2
Key Words: Arachnoiditis Ossificans, Intrathecal Pump, Calcification, Pain An abstract for this work was presented in poster format at the INS Conference May 29-May 31st in Edinburgh. Disclosures: Dr. Mammis is a paid consultant for Medtronic, St. Jude medical, and Nevro. No financial support was given for this study
1
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
Abstract
RI PT
A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans
SC
We present a case of delayed progression of adhesive arachnoiditis to arachnoiditis ossificans (AO) in a patient being treated with a high dose polypharmaceutical intrathecal regimen. The
M AN U
patient is a 39-year-old Caucasian male who was implanted with an intrathecal pump in 2006 to control severe low back pain and administered intrathecal pain medication for a period of 10 years. In 2016, he developed new onset radicular pain and worsened sensation in his lower extremities. A CT scan of the lumbar spine at that time demonstrated profound calcification of
TE D
the arachnoid consistent with a diagnosis of AO. It was presumed that prolonged high dose intrathecal medication precipitated this condition and his intrathecal medications were titrated down with removal of the pump. It is unlikely that his condition occurred as a result of prior
EP
surgery, with the more likely cause being hyperplasia of the spinal arachnoid, leading to scarring and calcification, due to the high dose intrathecal regimen. This case highlights the delayed
AC C
progression from stable arachnoiditis to AO concurring with a regimen of high dose intrathecal medications. Clinicians should closely monitor patients undergoing intrathecal drug administration, particularly at elevated doses, for indications of damage to the spinal arachnoid mater.
Introduction
2
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Arachnoiditis ossificans (AO) is defined by calcification of the spinal arachnoid, particularly in the lumbosacral or thoracic region, occurring secondary to chronic metaplastic changes which may lead to significant neurological symptoms from progressive neural
RI PT
compression.1,2,4 It is theorized that unchecked proliferation of arachnoid cells leads to dense collagen deposits which scar the meninges, promoting osteoblastic growth and subsequent calcification.3 It is considered to be the end-stage of adhesive arachnoiditis.9 These changes are
SC
often accompanied by lower back pain, leg pain, and sensory disturbances due to compression of the involved nerve roots. The exact cause of the condition remains unknown; however, it is
M AN U
believed that AO may occur secondary to prior spinal trauma including surgery, infection, and spinal anesthesia.1,4 We are presenting a case of delayed-onset AO which occurred after a long period of stable adhesive arachnoiditis, possibly due to additional inflammation caused by
TE D
elevated levels of intrathecal medication. This etiology of AO has not been previously reported.
Case Description
EP
A 39-year-old Caucasian male presented in 2016 with complaints of severe low back pain. Past medical history includes a diagnosis of osteoporosis at age 14. Complete surgical
AC C
history is documented in Table 1. In September of 2003 the patient underwent an L3-L4 right sided lumbar discectomy for a herniated disc. Following surgery, an MRI showed the development of adhesive arachnoiditis (Figure 1), and in December of 2003, the patient underwent L3-L5 laminectomies with extradural decompression of the thecal sac and intradural exploration for lysis of adhesive arachnoiditic lesions. There was a poor response to the procedure, and in July of 2004, he underwent a 3-level fusion with interbody devices at each
3
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication level (L3-L4, L4-L5, L5-S1). Spinal fusion was demonstrated on postoperative plain radiographs (Figure 2). At this point, the patient was diagnosed with failed back surgery syndrome and, having previously failed an attempt at spinal cord stimulation, he was sent for pain management.
RI PT
While the patient previously had arachnoid inflammation in the lower lumbar region, a CT scan of the lumbar spine, obtained in August of 2004, revealed no arachnoid calcifications (Figure 3). In July of 2006, the patient underwent an uncomplicated intrathecal pump implantation to
SC
control his progressive pain. The catheter was placed between the L1 and L2 laminae. Prior to pump placement, physical examination revealed 5-/5 strength in all lower extremity muscle
M AN U
groups with the exception of the left extensor hallucis longus, which was 0/5. Lower extremity deep tendon reflexes were depressed and sensation was diminished bilaterally on pinprick testing in the L4-S1 dermatomes. One-month post-implant, the patient reported that his pain was well controlled; however, the patient moved to another state and was lost to follow-up for two years
TE D
until he was seen again in October of 2008. At this point, the patient reported recurrence of low back pain despite the continued use of his intrathecal pump. Plain radiographs were obtained annually but were not specific for any pathology. The
EP
spinal instrumentation was well positioned and a solid spinal fusion was observed. Follow-up MRI, in 2009, showed septations within the thecal sac and thickened, clumped nerve roots from
AC C
L3 throughout the thecal sac distally consistent with severe arachnoiditis (Figure 4a and 4b). A small linear focus of increased T1 signal in the thecal sac at the L5 level suggested a small focus of calcification. An MRI, obtained in 2011, revealed similar levels of adhesive arachnoiditis; however, the focus of calcification is slightly larger compared to the prior MRI (Figure 4c and 4d).
4
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication During a follow up exam in December of 2016, the patient reported exacerbation of his pre-existing pain. The patient reported numbness, paresthesias, and weakness in his lower extremities. On physical exam, strength was 4+/5 in the right iliopsoas, 5-/5 in the left iliopsoas,
RI PT
5/5 bilaterally in the quadriceps and hamstrings, 5/5 in the right ankle dorsiflexor, 4/5 in the left ankle dorsiflexor, 5/5 in the right ankle plantar, and 5-/5 in the left ankle plantar. Deep tendon reflexes were absent bilaterally. Sensation was diminished throughout the lower extremities. A
SC
CT scan of the lumbar spine showed profound calcification of the arachnoid consistent with a diagnosis of arachnoiditis ossificans (Figure 5). By this point the patient’s intrathecal medication
M AN U
regimen included: 24.506 mg/day hydromorphone, 447.4 mcg/day baclofen, 3.3431 mg/day bupivacaine, and six optional daily bolus doses of 0.100 mg hydromorphone, 1.8 mcg baclofen, and 0.013 mg bupivacaine.
Calcification of the arachnoid was attributed to the significantly elevated intrathecal drug
TE D
levels. The medications were actively titrated down with subsequent removal of both the pump and the intrathecal catheter. Future treatment being considered at this time will be implantation of a dorsal root ganglion stimulator to control the recurrent pain. While surgical management has
EP
been used in the past, invasive resection of an end-stage inflammatory mass may only serve to inflame the region further.
8
There currently exists no consensus on the ideal therapy for
AC C
arachnoiditis ossificans.1
Discussion
While small calcifications within the spinal canal can commonly form in the natural course of aging, they are frequently asymptomatic and pathophysiologically distinct from AO.
5
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Arachnoiditis ossificans is extremely rare in any clinical setting with fewer than 100 reported cases appearing in the literature over 80 years.8 The condition most commonly occurs in the thoracic region, although formation in the lumbar region has also been documented.8 There is
RI PT
often a predisposing insult in the patient’s medical history which is linked to the development of AO. These include surgery, trauma, use of intrathecal contrast, local anesthetics, blood in the thecal sac, infection, or other degenerative spinal pathology.7 There are no previously
SC
documented associations between AO and intrathecal infusion devices. AO has been classified as type III arachnoiditis according to the Delamarter criterion which indicates complete
M AN U
opacification of the thecal sac at a minimum of one vertebral level.5
It is rare for adhesive arachnoiditis to progress to AO, and the natural history of the disorder is currently unknown.8
The calcific changes within the lumbar spine occurred in
conjunction with the intrathecal polypharmaceutical regimen without any significant changes in
TE D
radiographically evident inflammation (Figure 4). As such, we believe that this pathophysiological change occurred as a result of the high dose medications causing localized calcification to the regionally susceptible lumbar spine. While it is possible calcification of the
EP
lumbar arachnoid occurred from delayed changes due to the patient’s multiple surgeries, CT scan prior to placement of the intrathecal pump showed no evidence of calcification, and the
AC C
arachnoiditis remained relatively stable on MRI during a period when lesser doses of standard intrathecal pain medications were being administered (Figures 3 and 4). Additionally, there was no off-label use of BMP in any of his prior surgeries ruling out BMP induced ectopic bone formation. It is far more likely that the use of multiple high dose intrathecal medications caused progressive calcification of the previously stable adhesive arachnoiditis leading to the incidental complication of AO.2
6
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Although new onset radicular pain has never been associated with intrathecal drug administration, it has previously been attributed to granuloma formation secondary to the inflammatory effect of opioids.3 With this in mind, it appears quite possible that this effect could
RI PT
translate throughout the spinal canal. While the calcifications occurred distal to the catheter tip, it is hypothesized that a settling effect occurred over time which led to a local buildup of drug in the lower lumbar region. It is unclear which drug or combination of drugs precipitated this
SC
condition; however, it is noteworthy that hydromorphone dosing was significantly elevated from the recommended maximal dose of 10 mg/day6, and highly concentrated opioids have shown the
M AN U
capability to produce inflammatory masses.3 Additionally, the long-term interactions between the various medications utilized in this case are not well understood. It must be noted, however, that the overwhelming majority of patients who undergo intrathecal pump implantation do not develop AO, and thus this may be a chance association. A large-scale study of this patient
TE D
population is necessary before any definitive conclusions can be made. This case highlights an unusual progression from stable arachnoiditis to AO. In the future, it is critical that clinicians consider AO when managing intrathecal dosing regimens in
EP
patients with prior arachnoid inflammation, and screen for physiological changes in their patients
AC C
throughout treatment.
Appendix:
Figure 1: T2 sagittal MRI of the lumbar spine from 2003 showing degenerative disc disease at L3-L4, L4-L5 and L5-S1 with diffuse disc bulges, central canal stenosis and neuroforaminal narrowing. No evidence of arachnoiditis
7
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
Figure 2: Anteroposterior (A) and lateral (B) films showing proper positioning of the
RI PT
instrumentation and solid spinal fusion at L3-L4, L4-L5 and L5-S1.
Figure 3: CT Lumbar spine in 2004 status post laminectomies from L3 through L5 with pedicle screws, posterior rods, and interbody cages at each level from L3 through S1. There is a small
SC
amount of calcification or bone fragments in the central spinal canal, the location cannot be
M AN U
discerned due to artifact from hardware. Pedicle screws are well-located.
Figure 4: A and B: T2 sagittal and axial MRI of the lumbar spine from 2009 showing septations within the thecal sac and thickened, clumped nerve roots in the thecal sac from L3 through the distal thecal sac consistent with severe arachnoiditis. There is a small linear focus of increased
TE D
T1 signal in the thecal sac at the L5 level suggesting calcification. Axial image shows the empty sac sign of arachnoiditis at the L3 level. Artifact is due to screws C and D: T2 sagittal and axial MRI from 2011. The arachnoiditis within the thecal sac does not appear significantly different;
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MRI in 2009.
EP
however, the calcification in the thecal sac is thicker and larger in size compared to the prior
Figure 5: CT lumbar spine in 2017 showing severe calcification in the spinal canal consistent with a diagnosis of AO. The calcifications encase the thecal sac from the L3 to L5 level. This has progressed appreciably compared with the prior MRI from 2011
8
ACCEPTED MANUSCRIPT
4. 5. 6. 7.
8.
9.
9
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3.
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2.
Abrams J, Li G, Mindea SA, Haynes CM, Cheng I: Arachnoid ossificans containing metaplastic hematopoietic marrow resulting in diffuse thoracic intrathecal cysts and severe myelopathy. Eur Spine J 21 Suppl 4:S436-440, 2012 Bagley JH, Owens TR, Grunch BH, Moreno JR, Bagley CA: Arachnoiditis ossificans of the thoracic spine. J Clin Neurosci 21:386-389, 2014 Belverud S, Mogilner A, Schulder M: Intrathecal pumps. Neurotherapeutics 5:114-122, 2008 Chan CC, Lau PY, Sun LK, Lo SS: Arachnoiditis ossificans. Hong Kong Med J 15:146148, 2009 Delamarter RB, Ross JS, Masaryk TJ, Modic MT, Bohlman HH: Diagnosis of lumbar arachnoiditis by magnetic resonance imaging. Spine (Phila Pa 1976) 15:304-310, 1990 Knight KH, Brand FM, McHaourab AS, Veneziano G: Implantable intrathecal pumps for chronic pain: highlights and updates. Croat Med J 48:22-34, 2007 Kochany JZ, Tran ND, Sarria JE: Increasing back and radicular pain 2 years following intrathecal pump implantation with review of arachnoiditis. Pain Med 14:1658-1663, 2013 Maulucci CM, Ghobrial GM, Oppenlander ME, Flanders AE, Vaccaro AR, Harrop JS: Arachnoiditis ossificans: clinical series and review of the literature. Clin Neurol Neurosurg 124:16-20, 2014 Moens M, De Smedt A, Marien P, Brouns R: Intrathecal bupivacaine for arachnoiditis ossificans: a case report. Clin Neurol Neurosurg 115:1162-1163, 2013
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References
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Arachnoiditis Ossificans Secondary to Intrathecal Medication
ACCEPTED MANUSCRIPT
Table 1: Patient Procedures and Advanced Imaging
Date
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Discectomy L1-L2, L2-L3 Oct-99 Discectomy L3-L4, L4-L5, L5-S1 Aug-00 SCS Implant Jan-02 MR Lumbar Spine Aug-03 Discectomy Right L3-L4 Sep-03 Laminectomy L3-L4, L4-L5 with Lysis of Intradural Adhesions Dec-03 MR Lumbar Spine Feb-04 MR Lumbar Spine Jul-04 PLIF L3-L4, L4-L5, L5-S1 with SCS Explant Jul-04 CT Lumbar Spine Aug-04 Intrathecal Pump Implant Jul-06 MR Lumbar Spine Apr-09 MR Lumbar Spine May-11 Pump Battery Change Feb-13 Pump Removal with Retained Catheter Jan-17 CT Lumbar Spine Feb-17 Pump Catheter Removal Feb-17
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Procedure
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SCS: Spinal Cord Stimulator, PLIF: Posterior Lumbar Interbody Fusion
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
Highlights: We present the late progression of adhesive arachnoiditis to arachnoiditis ossificans
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High dose intrathecal medications may have inflammatory effects within the thecal sac
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EP
TE D
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SC
Imaging and screening in intrathecal pump patients may prevent serious morbidity
ACCEPTED MANUSCRIPT
Abbreviation List:
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TE D
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AO: Arachnoiditis Ossificans, CT: Computed Tomography, MRI: Magnetic Resonance Imaging
S1878-8750(18)30916-1
DOI:
10.1016/j.wneu.2018.04.196
Reference:
WNEU 8032
To appear in:
World Neurosurgery
Received Date: 24 February 2018 Revised Date:
24 April 2018
Accepted Date: 25 April 2018
Please cite this article as: Ward M, Mammis A, Barry MT, Heary RF, A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans, World Neurosurgery (2018), doi: 10.1016/ j.wneu.2018.04.196. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
M AN U
SC
RI PT
Max Ward 180 West Market Street, Newark NJ, 08807 [email protected] 908-698-3475
A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans Max Ward1 BS, Antonios Mammis1 MD, Maureen T. Barry2 MD, Robert F. Heary1 MD 1 Rutgers-New Jersey Medical School Department of Neurological Surgery Newark, New Jersey Department of Radiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina
AC C
EP
TE D
2
Key Words: Arachnoiditis Ossificans, Intrathecal Pump, Calcification, Pain An abstract for this work was presented in poster format at the INS Conference May 29-May 31st in Edinburgh. Disclosures: Dr. Mammis is a paid consultant for Medtronic, St. Jude medical, and Nevro. No financial support was given for this study
1
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
Abstract
RI PT
A Novel Association Between Intrathecal Drug Administration and Arachnoiditis Ossificans
SC
We present a case of delayed progression of adhesive arachnoiditis to arachnoiditis ossificans (AO) in a patient being treated with a high dose polypharmaceutical intrathecal regimen. The
M AN U
patient is a 39-year-old Caucasian male who was implanted with an intrathecal pump in 2006 to control severe low back pain and administered intrathecal pain medication for a period of 10 years. In 2016, he developed new onset radicular pain and worsened sensation in his lower extremities. A CT scan of the lumbar spine at that time demonstrated profound calcification of
TE D
the arachnoid consistent with a diagnosis of AO. It was presumed that prolonged high dose intrathecal medication precipitated this condition and his intrathecal medications were titrated down with removal of the pump. It is unlikely that his condition occurred as a result of prior
EP
surgery, with the more likely cause being hyperplasia of the spinal arachnoid, leading to scarring and calcification, due to the high dose intrathecal regimen. This case highlights the delayed
AC C
progression from stable arachnoiditis to AO concurring with a regimen of high dose intrathecal medications. Clinicians should closely monitor patients undergoing intrathecal drug administration, particularly at elevated doses, for indications of damage to the spinal arachnoid mater.
Introduction
2
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Arachnoiditis ossificans (AO) is defined by calcification of the spinal arachnoid, particularly in the lumbosacral or thoracic region, occurring secondary to chronic metaplastic changes which may lead to significant neurological symptoms from progressive neural
RI PT
compression.1,2,4 It is theorized that unchecked proliferation of arachnoid cells leads to dense collagen deposits which scar the meninges, promoting osteoblastic growth and subsequent calcification.3 It is considered to be the end-stage of adhesive arachnoiditis.9 These changes are
SC
often accompanied by lower back pain, leg pain, and sensory disturbances due to compression of the involved nerve roots. The exact cause of the condition remains unknown; however, it is
M AN U
believed that AO may occur secondary to prior spinal trauma including surgery, infection, and spinal anesthesia.1,4 We are presenting a case of delayed-onset AO which occurred after a long period of stable adhesive arachnoiditis, possibly due to additional inflammation caused by
TE D
elevated levels of intrathecal medication. This etiology of AO has not been previously reported.
Case Description
EP
A 39-year-old Caucasian male presented in 2016 with complaints of severe low back pain. Past medical history includes a diagnosis of osteoporosis at age 14. Complete surgical
AC C
history is documented in Table 1. In September of 2003 the patient underwent an L3-L4 right sided lumbar discectomy for a herniated disc. Following surgery, an MRI showed the development of adhesive arachnoiditis (Figure 1), and in December of 2003, the patient underwent L3-L5 laminectomies with extradural decompression of the thecal sac and intradural exploration for lysis of adhesive arachnoiditic lesions. There was a poor response to the procedure, and in July of 2004, he underwent a 3-level fusion with interbody devices at each
3
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication level (L3-L4, L4-L5, L5-S1). Spinal fusion was demonstrated on postoperative plain radiographs (Figure 2). At this point, the patient was diagnosed with failed back surgery syndrome and, having previously failed an attempt at spinal cord stimulation, he was sent for pain management.
RI PT
While the patient previously had arachnoid inflammation in the lower lumbar region, a CT scan of the lumbar spine, obtained in August of 2004, revealed no arachnoid calcifications (Figure 3). In July of 2006, the patient underwent an uncomplicated intrathecal pump implantation to
SC
control his progressive pain. The catheter was placed between the L1 and L2 laminae. Prior to pump placement, physical examination revealed 5-/5 strength in all lower extremity muscle
M AN U
groups with the exception of the left extensor hallucis longus, which was 0/5. Lower extremity deep tendon reflexes were depressed and sensation was diminished bilaterally on pinprick testing in the L4-S1 dermatomes. One-month post-implant, the patient reported that his pain was well controlled; however, the patient moved to another state and was lost to follow-up for two years
TE D
until he was seen again in October of 2008. At this point, the patient reported recurrence of low back pain despite the continued use of his intrathecal pump. Plain radiographs were obtained annually but were not specific for any pathology. The
EP
spinal instrumentation was well positioned and a solid spinal fusion was observed. Follow-up MRI, in 2009, showed septations within the thecal sac and thickened, clumped nerve roots from
AC C
L3 throughout the thecal sac distally consistent with severe arachnoiditis (Figure 4a and 4b). A small linear focus of increased T1 signal in the thecal sac at the L5 level suggested a small focus of calcification. An MRI, obtained in 2011, revealed similar levels of adhesive arachnoiditis; however, the focus of calcification is slightly larger compared to the prior MRI (Figure 4c and 4d).
4
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication During a follow up exam in December of 2016, the patient reported exacerbation of his pre-existing pain. The patient reported numbness, paresthesias, and weakness in his lower extremities. On physical exam, strength was 4+/5 in the right iliopsoas, 5-/5 in the left iliopsoas,
RI PT
5/5 bilaterally in the quadriceps and hamstrings, 5/5 in the right ankle dorsiflexor, 4/5 in the left ankle dorsiflexor, 5/5 in the right ankle plantar, and 5-/5 in the left ankle plantar. Deep tendon reflexes were absent bilaterally. Sensation was diminished throughout the lower extremities. A
SC
CT scan of the lumbar spine showed profound calcification of the arachnoid consistent with a diagnosis of arachnoiditis ossificans (Figure 5). By this point the patient’s intrathecal medication
M AN U
regimen included: 24.506 mg/day hydromorphone, 447.4 mcg/day baclofen, 3.3431 mg/day bupivacaine, and six optional daily bolus doses of 0.100 mg hydromorphone, 1.8 mcg baclofen, and 0.013 mg bupivacaine.
Calcification of the arachnoid was attributed to the significantly elevated intrathecal drug
TE D
levels. The medications were actively titrated down with subsequent removal of both the pump and the intrathecal catheter. Future treatment being considered at this time will be implantation of a dorsal root ganglion stimulator to control the recurrent pain. While surgical management has
EP
been used in the past, invasive resection of an end-stage inflammatory mass may only serve to inflame the region further.
8
There currently exists no consensus on the ideal therapy for
AC C
arachnoiditis ossificans.1
Discussion
While small calcifications within the spinal canal can commonly form in the natural course of aging, they are frequently asymptomatic and pathophysiologically distinct from AO.
5
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Arachnoiditis ossificans is extremely rare in any clinical setting with fewer than 100 reported cases appearing in the literature over 80 years.8 The condition most commonly occurs in the thoracic region, although formation in the lumbar region has also been documented.8 There is
RI PT
often a predisposing insult in the patient’s medical history which is linked to the development of AO. These include surgery, trauma, use of intrathecal contrast, local anesthetics, blood in the thecal sac, infection, or other degenerative spinal pathology.7 There are no previously
SC
documented associations between AO and intrathecal infusion devices. AO has been classified as type III arachnoiditis according to the Delamarter criterion which indicates complete
M AN U
opacification of the thecal sac at a minimum of one vertebral level.5
It is rare for adhesive arachnoiditis to progress to AO, and the natural history of the disorder is currently unknown.8
The calcific changes within the lumbar spine occurred in
conjunction with the intrathecal polypharmaceutical regimen without any significant changes in
TE D
radiographically evident inflammation (Figure 4). As such, we believe that this pathophysiological change occurred as a result of the high dose medications causing localized calcification to the regionally susceptible lumbar spine. While it is possible calcification of the
EP
lumbar arachnoid occurred from delayed changes due to the patient’s multiple surgeries, CT scan prior to placement of the intrathecal pump showed no evidence of calcification, and the
AC C
arachnoiditis remained relatively stable on MRI during a period when lesser doses of standard intrathecal pain medications were being administered (Figures 3 and 4). Additionally, there was no off-label use of BMP in any of his prior surgeries ruling out BMP induced ectopic bone formation. It is far more likely that the use of multiple high dose intrathecal medications caused progressive calcification of the previously stable adhesive arachnoiditis leading to the incidental complication of AO.2
6
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication Although new onset radicular pain has never been associated with intrathecal drug administration, it has previously been attributed to granuloma formation secondary to the inflammatory effect of opioids.3 With this in mind, it appears quite possible that this effect could
RI PT
translate throughout the spinal canal. While the calcifications occurred distal to the catheter tip, it is hypothesized that a settling effect occurred over time which led to a local buildup of drug in the lower lumbar region. It is unclear which drug or combination of drugs precipitated this
SC
condition; however, it is noteworthy that hydromorphone dosing was significantly elevated from the recommended maximal dose of 10 mg/day6, and highly concentrated opioids have shown the
M AN U
capability to produce inflammatory masses.3 Additionally, the long-term interactions between the various medications utilized in this case are not well understood. It must be noted, however, that the overwhelming majority of patients who undergo intrathecal pump implantation do not develop AO, and thus this may be a chance association. A large-scale study of this patient
TE D
population is necessary before any definitive conclusions can be made. This case highlights an unusual progression from stable arachnoiditis to AO. In the future, it is critical that clinicians consider AO when managing intrathecal dosing regimens in
EP
patients with prior arachnoid inflammation, and screen for physiological changes in their patients
AC C
throughout treatment.
Appendix:
Figure 1: T2 sagittal MRI of the lumbar spine from 2003 showing degenerative disc disease at L3-L4, L4-L5 and L5-S1 with diffuse disc bulges, central canal stenosis and neuroforaminal narrowing. No evidence of arachnoiditis
7
ACCEPTED MANUSCRIPT Arachnoiditis Ossificans Secondary to Intrathecal Medication
Figure 2: Anteroposterior (A) and lateral (B) films showing proper positioning of the
RI PT
instrumentation and solid spinal fusion at L3-L4, L4-L5 and L5-S1.
Figure 3: CT Lumbar spine in 2004 status post laminectomies from L3 through L5 with pedicle screws, posterior rods, and interbody cages at each level from L3 through S1. There is a small
SC
amount of calcification or bone fragments in the central spinal canal, the location cannot be
M AN U
discerned due to artifact from hardware. Pedicle screws are well-located.
Figure 4: A and B: T2 sagittal and axial MRI of the lumbar spine from 2009 showing septations within the thecal sac and thickened, clumped nerve roots in the thecal sac from L3 through the distal thecal sac consistent with severe arachnoiditis. There is a small linear focus of increased
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Figure 5: CT lumbar spine in 2017 showing severe calcification in the spinal canal consistent with a diagnosis of AO. The calcifications encase the thecal sac from the L3 to L5 level. This has progressed appreciably compared with the prior MRI from 2011
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Abrams J, Li G, Mindea SA, Haynes CM, Cheng I: Arachnoid ossificans containing metaplastic hematopoietic marrow resulting in diffuse thoracic intrathecal cysts and severe myelopathy. Eur Spine J 21 Suppl 4:S436-440, 2012 Bagley JH, Owens TR, Grunch BH, Moreno JR, Bagley CA: Arachnoiditis ossificans of the thoracic spine. J Clin Neurosci 21:386-389, 2014 Belverud S, Mogilner A, Schulder M: Intrathecal pumps. Neurotherapeutics 5:114-122, 2008 Chan CC, Lau PY, Sun LK, Lo SS: Arachnoiditis ossificans. Hong Kong Med J 15:146148, 2009 Delamarter RB, Ross JS, Masaryk TJ, Modic MT, Bohlman HH: Diagnosis of lumbar arachnoiditis by magnetic resonance imaging. Spine (Phila Pa 1976) 15:304-310, 1990 Knight KH, Brand FM, McHaourab AS, Veneziano G: Implantable intrathecal pumps for chronic pain: highlights and updates. Croat Med J 48:22-34, 2007 Kochany JZ, Tran ND, Sarria JE: Increasing back and radicular pain 2 years following intrathecal pump implantation with review of arachnoiditis. Pain Med 14:1658-1663, 2013 Maulucci CM, Ghobrial GM, Oppenlander ME, Flanders AE, Vaccaro AR, Harrop JS: Arachnoiditis ossificans: clinical series and review of the literature. Clin Neurol Neurosurg 124:16-20, 2014 Moens M, De Smedt A, Marien P, Brouns R: Intrathecal bupivacaine for arachnoiditis ossificans: a case report. Clin Neurol Neurosurg 115:1162-1163, 2013
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Arachnoiditis Ossificans Secondary to Intrathecal Medication
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Table 1: Patient Procedures and Advanced Imaging
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Discectomy L1-L2, L2-L3 Oct-99 Discectomy L3-L4, L4-L5, L5-S1 Aug-00 SCS Implant Jan-02 MR Lumbar Spine Aug-03 Discectomy Right L3-L4 Sep-03 Laminectomy L3-L4, L4-L5 with Lysis of Intradural Adhesions Dec-03 MR Lumbar Spine Feb-04 MR Lumbar Spine Jul-04 PLIF L3-L4, L4-L5, L5-S1 with SCS Explant Jul-04 CT Lumbar Spine Aug-04 Intrathecal Pump Implant Jul-06 MR Lumbar Spine Apr-09 MR Lumbar Spine May-11 Pump Battery Change Feb-13 Pump Removal with Retained Catheter Jan-17 CT Lumbar Spine Feb-17 Pump Catheter Removal Feb-17
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SCS: Spinal Cord Stimulator, PLIF: Posterior Lumbar Interbody Fusion
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Highlights: We present the late progression of adhesive arachnoiditis to arachnoiditis ossificans
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High dose intrathecal medications may have inflammatory effects within the thecal sac
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Imaging and screening in intrathecal pump patients may prevent serious morbidity
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Abbreviation List:
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AO: Arachnoiditis Ossificans, CT: Computed Tomography, MRI: Magnetic Resonance Imaging